This disclosure generally relates to formulations containing active pharmaceutical ingredients that have low solubility in water. In aspects, the formulations are solid oral dosage forms. Embodiments of formulations include orally disintegrating tablets.
Many therapeutically useful drug substances have low aqueous solubility and/or low intestinal permeability. These properties complicate the design of dosage forms for delivering the drug substances. The Biopharmaceutics Classification System (“BCS”) has been developed to describe drug substances by their solubility and permeability properties:
Class I—high permeability, high solubility drugs that are well absorbed.
Class II—high permeability, low solubility drugs having bioavailability that is limited by the solubilization rate.
Class III—low permeability, high solubility drugs having bioavailability that is limited by the permeation rate.
Class IV—low permeability, low solubility drugs having poor bioavailability and high variability of pharmacokinetics parameters (e.g., AUC and Cmax).
A drug is considered to be highly soluble under the BCS when its highest unit dosage strength is soluble in 250 mL or less of aqueous media over the pH range of 1 to 7.5. Many drug substances, however, fall within Classes II and IV. Formulating dosage forms to deliver such drugs, particularly when larger amounts of the drugs must be delivered in each dose, is very challenging. The absolute drug solubility is not always the most important parameter, since residence times in various sites within the gastrointestinal system after oral administration vary, and it is usually necessary to have a drug in solution during its transit through the particular sites where it can be systemically absorbed. Examples of drugs having low solubility are those that form solutions with water having concentrations no greater than 1 mg/mL, or no greater than 0.1 mg/mL.
Various approaches for improving the solubility properties of drugs have been used. For many substances, solubility can be enhanced by reducing the particle sizes; an increased particle surface area generally results in a more rapid dissolution rate. Sometimes, different polymorphic forms, including crystalline, solvated, and amorphous forms, will have different solubilities and a suitable form can be chosen to meet a specific requirement. However, these approaches are not without difficulties, since very small particles generally have poor flow and handling properties that can affect drug content uniformity, and many polymorphic forms do not have sufficient physical stability to undergo formulation processing and the subsequent storage over a typical product shelf life, without converting to a different form.
The amorphous particles can have increased solubility by overcoming crystal lattice energy. Typically, amorphous drug particles are thermodynamically metastable compared to crystalline states of the substance, but can have significantly enhanced solubility and bioavailability. Solubility can be further classified as equilibrium and supersaturation solubilities. “Equilibrium solubility” is the solubility of the substance in a specific fluid environment, in the absence of a solubilization aid. “Supersaturation” refers to the solubility state of a substance in excess of its equilibrium solubility, characterized by a solubility that is greater than that defined by native solubility of the substance in a given fluid environment. By converting a drug from a crystalline to amorphous form, it is possible to achieve a supersaturation solubility, which in turn can enhance bioavailability. However, significant challenges of chemical and physical drug instability remain. The amorphous state can be viewed as a pseudo-solution state demonstrating greater chemical reactivity, which is reflected in reduced physical and chemical stability and shelf-life. Certain drugs have been commercialized in the amorphous state, where the amorphous form of the drug substance either has acceptable stability over the normal shelf-life of the product, or can be stabilized by other formulation components. In addition, some drugs have been successfully commercialized in a thermodynamically metastable crystalline state.
Amorphous solid dispersion have been used to stabilize amorphous material. A solid dispersion is formed from at least two different components, generally (a) a polymer that can be either crystalline or amorphous and (b) a hydrophobic drug that can be dispersed molecularly, in amorphous particles (clusters) or in crystalline particles. Polymers can improve the physical stability of amorphous drugs in solid dispersions by increasing the glass transition temperature (Tg) of the miscible mixture, thus reducing the molecular mobility at usual storage temperatures, or by interacting specifically with functional groups of the drugs. For a polymer to be effective in preventing crystallization, it has to be molecularly miscible with the drug. However, to date, limitations in the development of solid dispersions are predominantly due to physical instability of these systems. Polymeric materials are not in thermodynamic equilibrium below their Tg, so the solid polymer approaches its more stable state (lower energy). Also, the effect of moisture on the storage stability of amorphous material is very important as it may increase drug mobility and promote drug crystallization. In addition, many of the polymers used in solid dispersions can absorb moisture, which may result in phase separation, crystal growth or conversion from the amorphous to the crystalline state or from a metastable crystalline form to a more stable structure during storage, all of which may result in decreased solubility and dissolution rate.
For certain patients, swallowing a typical solid pharmaceutical dosage form is difficult. These patients can be elderly, very young, suffering from psychiatric disorders, have oral or esophageal dysfunctions or deformities, etc. When a solid dosage form is preferable, such as to reduce the chances for dosing errors, products have been developed that rapidly disintegrate while being retained in the oral cavity. This disintegration can be a decomposition of the tablet matrix into very small particles and/or dissolution of the matrix in saliva, thereby facilitating swallowing.
An orally disintegrating tablet (“ODT”) has been defined by the United States Food and Drug Administration as a solid dosage form containing a medicinal substance that disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue. In general, disintegration is expected to occur within about 30 seconds after the dosage form enters the oral cavity. Such dosage forms are useful for treating pediatric and geriatric patients having difficulties with swallowing tablets, capsules, etc., as well as psychiatric patients having an aversion to the customary swallowed solid forms. The action of saliva is sufficient to achieve the desired result, and mechanical disintegration, such as by chewing, is not required. Desirably, no external liquids will be necessary for swallowing the disintegrated dosage form. An ODT is also sometimes called an “orodispersible” tablet.
The ODT dosage form has certain important requirements, for patient acceptability; these requirements are in addition to the proper disintegration times. Frequently, the taste of the drug substance will be masked, since many substances have bitter or otherwise unpleasant tastes. Also, the mouth feel of the disintegrated tablet is important, so grittiness and the sensation of a residue in the mouth after swallowing should be avoided.
There are several techniques currently in use for making ODT products, including freeze drying or lyophilization of solutions or suspensions, compression of powder blends, molding of melts or pastes, melt granulation, and others. Most of the techniques will prepare tablets that are rather porous to aqueous fluids, thereby promoting rapid disintegration of the matrix in saliva.
An early approach to preparing an orally disintegrating tablet was described in U.S. Pat. No. 4,758,598, where a drug is physically trapped in a freeze-dried matrix composed of a filler (e.g., mannitol) and a polymer (e.g., gelatin). The product is a rather fragile, low-density porous wafer, packaged in the plastic tray where it was formed in a lyophilizer. More recently, U.S. Pat. No. 5,763,476 described an asenapine maleate product prepared in this manner; the drug will be released into saliva and, due to its moderate aqueous solubility, undergoes systemic absorption through the oral mucosa. Other current products are manufactured using this technique.
Although the perception may be that rapid disintegration leads to rapid rates of absorption and bioavailability, this is frequently not observed with poorly soluble drugs. Following dosage form disintegration, it still is necessary for the drug to dissolve before it can be absorbed. It would be advantageous to simultaneously provide rapid disintegration and a drug solubility enhancement in a dosage form.
There is a continuing need for improved pharmaceutical formulations containing low solubility drugs, providing features of oral fast disintegration and higher drug solubility, and therefore faster onset of action for poorly soluble drugs for certain therapeutic classes to improve patient compliance.